This invention relates to neurotrophic, low molecular weight, small molecule heterocyclic ketone and thioester compounds, and their use for effecting neuronal activities in animals, including treating neurological disorders.
It has been found that picomolar concentrations of an immunosuppressant, such as FK506 or rapamycin, stimulates neurite outgrowth in PC12 cells and sensory neurons, namely dorsal root ganglion cells (DRGs). Lyons et al., Proc. of Natl. Acad. Sci., 1994, vol. 91, pp. 3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury and results in functional recovery in animals with sciatic nerve lesions.
Studies have demonstrated that neurodegenerative disorders, such as senile dementia of the Alzheimer""s type (SDAT or Alzheimer""s disease), Parkinson""s disease and amyotrophic lateral sclerosis (ALS), may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular population of neurons affected in the disorder. Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified.
For example, it has been hypothesized that Alzheimer""s disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of degenerating neuronal populations.
Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity. However, when administered chronically, immunosuppressants exhibit a number of potentially serious side effects, including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephrol., 1991, 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non-localized headaches (De Groen et al., N. Engl. J. Med., 1987, 317:861); and vascular hypertension, with complications resulting therefrom (Kahan et al., N. Engl. J. Med., 1989, 321:1725).
To avoid the drawbacks associated with use of large molecule proteins and/or immunosuppressants, the present invention provides small molecule compounds for enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neurorral repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage associated with stroke; and neurological disorders relating to neurodegeneration, such as Parkinson""s disease, Huntington""s Disease, SDAT (Alzheimer""s disease) and amyotrophic lateral sclerosis (ALS).
The present invention relates to neurotrophic, low molecular weight, small molecule heterocyclic ketone or thioester compounds. In a preferred embodiment, the compounds are non-immunosuppressive. In another preferred embodiment, the compounds of the present invention have an affinity for FKBP-type immunophilins, such as FKBP12; and affinity binding or interaction may inhibit the prolyl-peptidyl cis-trans isomerase, or rotamase, activity of the binding protein.
The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of a neurotrophic, low molecular weight, small molecule heterocyclic ketone or thioester compound; and
(ii) a pharmaceutically acceptable carrier.
The present invention further relates to a method of effecting a neuronal activity in an animal, comprising administering to said animal an effective amount of a neurotrophic, low molecular weight, small molecule heterocyclic ketone or thioester compound.
Specifically, the present invention relates to a compound of formula II: 
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1 or 2;
X is O or S;
Z is selected from the group consisting of S, CH2, CHR1, CR1R2, and a bond;
R1, R2, and R3 are independently selected from the group consisting of C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, and Ar, wherein said R1, R2, or R3 is unsubstituted or substituted with one or more halo, trifluoromethyl, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, or Ar;
R4 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, and Ar; and
Ar is aryl.
The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of the compound of formula II; and
(ii) a pharmaceutically acceptable carrier.
The present invention further relates to a method of effecting a neuronal activity in an animal, comprising administering to said animal an effective amount of a compound of formula II.